Tyrosine kinase inhibitors in pulmonary arterial hypertension: a double-edge sword?

Semin Respir Crit Care Med. 2013 Oct;34(5):714-24. doi: 10.1055/s-0033-1356494. Epub 2013 Sep 13.

Abstract

New treatments for pulmonary arterial hypertension (PAH) are a crucial need. The increased proliferation, migration, and survival of pulmonary vascular cells within the pulmonary artery wall in PAH have allowed successful transposition of pathophysiological elements from oncologic researches. Next steps will require translation of these biological advances in PAH therapeutic arsenal and guidelines. This review synthesizes recent data concerning the role of receptor tyrosine kinases and their inhibitors in PAH, with implications in animal models and humans. Results of clinical trials are now accumulating to establish beneficial role of tyrosine kinase inhibitors (TKIs) in PAH and further findings are expected in the near future. Beside this curative approach, evidences of a possible TKI-induced cardiotoxicity are emerging. These safety issues raise concern about a potential amplified harmful effect in PAH, a pathology characterized by an underlying cardiac dysfunction. In addition, analyses of PAH registries shed light on a selective pulmonary vascular toxicity triggered by TKIs, especially dasatinib. These possible dual effects of the TKIs in PAH need to be taken in account for future pharmacological development of this therapeutic class in PAH.

Publication types

  • Review

MeSH terms

  • Apoptosis / physiology
  • Benzamides / therapeutic use
  • Cell Proliferation
  • Dasatinib
  • Endothelial Cells
  • ErbB Receptors / metabolism
  • Familial Primary Pulmonary Hypertension
  • Fibroblast Growth Factor 2 / metabolism
  • Fibroblasts
  • Humans
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / metabolism
  • Imatinib Mesylate
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle
  • Niacinamide / analogs & derivatives
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / therapeutic use
  • Piperazines / therapeutic use
  • Platelet-Derived Growth Factor / metabolism
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-kit / metabolism
  • Pulmonary Circulation
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Sorafenib
  • Thiazoles / adverse effects
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / metabolism
  • src-Family Kinases / metabolism

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Benzamides
  • Phenylurea Compounds
  • Piperazines
  • Platelet-Derived Growth Factor
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Niacinamide
  • Imatinib Mesylate
  • Sorafenib
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-kit
  • Receptor Protein-Tyrosine Kinases
  • src-Family Kinases
  • Dasatinib